IDO (indoleamine 2,3-dioxygenase) and/or TDO (tryptophan 2,3-dioxygenase) are heme-containing oxidoreductase enzymes which catalyze the initial and rate limiting step in the degradation of essential amino acid L-tryptophan to N-Formyl kenurenine. TDO is mainly expressed in liver tissue, and is responsible for regulating systemic tryptophan levels. IDO comprises two related enzymes IDO isozymes (IDO1, IDO2), and is widely expressed in numerous cells, such as neurons, astrocytes, microglia, especially antigen-presenting cells (macrophages and dendritic cells) at high level. IDO is also overexpressed in many different types of human tumor, facilitating the escape of malignant tumors from immune surveillance and promoting tumor growth. Three immunosuppressive mechanisms have been proposed for IDO-kenurenine pathway: 1. depletion of tryptophan directly inhibits activation and proliferation of effector T cells; 2. accumulation of toxic kynurenine, binding of kynurenine to the aryl hydrocarbon receptor enhance immune tolerance; 3. the induction of TReg cell. Tryptophan metabolism is critical for cell proliferation, inflammation and immunoregulation. Accelerated tryptophan breakdown favors tumor immune escape. Therefore IDO may represent an attractive therapeutic target in cancer immunotherapy.
There is also growing evidence that IDO inhibitors have potential therapeutic application in many other diseases, such as for treatment of infectious disease, inflammation, cataracts, endometriosis, pain, atherosclerosis, neurological or neuropsychiatric conditions such as depression, amyotrophic lateral sclerosis, Huntingdon's disease, Alzheimer's disease, multiple sclerosis, Parkinson's disease, etc.
Small molecule IDO inhibitors are being developed to treat the diseases mediated by IDO enzyme, and could be administered alone or in combination with chemotherapy or immunotherapy (PD-1, CTLA-4, PD-L1, etc.).